Investigating neuroinflammatory and neuronal mechanisms underlying the adverse neurological effects of brain radiotherapy

胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，是一种极度未满足需求的癌症。虽然临床结果仍然很差，但在过去20年中，总生存率有所上升，揭示了治疗相关神经系统并发症的破坏性影响。放射治疗（RT）是GBM中最有效的非手术治疗方式，也是大多数患者标准治疗的重要组成部分。RT是一种有效的治疗方法，但会导致不可逆转的认知障碍，并随着时间的推移而恶化。了解RT诱导的认知障碍的潜在机制将使我们能够直接针对患者的这种临床未满足的需求。高阶脑功能，如认知，依赖于局部和全局神经同步的完整性，并由GABA能网络介导。GABA能中间神经元与认知功能障碍相关的病理状态密切相关，其中小清蛋白中间神经元（PVI）亚组的缺陷与多种疾病模型中的认知下降相关。我们以前的研究（包括临床和临床前研究）表明，这些PVIs与精神分裂症和阿尔茨海默病相关的认知缺陷有关。在目前的项目中，我们计划进行纵向行为，电生理和定量尸检（免疫组织化学和自动化西方检测）研究，以调查RT治疗后认知缺陷的机制。该项目的另一个目的是评价合理的药理学干预（针对神经炎症和GABA能系统）对预防/逆转脑RT的神经毒性作用的影响。

Glioblastoma (GBM) is the most commonly occurring primary brain tumour and is a cancer of extreme unmet need. While clinical outcomes remain poor, overall survival has risen over the past 20 years, revealing the devastating impact of treatment-associated neurological complications. Radiotherapy (RT) is the most effective non-surgical treatment modality used in GBM and is a crucial component of standard of care for the majority of patients. RT is an effective treatment but causes irreversible cognitive impairments that worsen over time. Understanding the mechanisms underlying RT induced cognitive impairment will allow us to directly target this clinical unmet need in patients. Higher order brain functions such as cognition rely on the integrity of local and global neural synchrony and are mediated by GABAergic networks. GABAergic interneurons are strongly implicated in pathological states associated with cognitive dysfunction, with deficits in the parvalbumin interneuron (PVI) subset correlating with cognitive decline across multiple disease models. Our previous investigations (including both clinical and preclinical studies) have implicated these PVIs in the cognitive deficits associated with both schizophrenia and Alzheimer's disease. In the current project, we plan to undertake longitudinal behavioural, electrophysiological and quantitative post-mortem (immunohistochemical and automated western detection) studies to investigate mechanisms underlying cognitive deficits following RT treatment. A further aim of the project will be to evaluate the impact of rationale pharmacological interventions (targeting neuroinflammatory and GABAergic systems) to prevent/reverse the neurotoxic effects of brain RT